Medazepam and propantheline composition

ABSTRACT

Compositions comprising medazepam and propantheline halide, useful in treating gastrointestinal disorders are disclosed.

United States Patent Lerner et al.

MEDAZEPAM AND PROPANTHELINE COMPOSITION Inventors: lrwin Lerner, West Caldwell; Robert Paul McGrath, Wayne, both of NJ.

Hoffman-La Roche, Inc., Nutley, NJ.

The portion of the term of this patent subsequent to Oct. 24, l989, has been disclaimed.

Filed: May 6, 1971 Appl. No.: 141,034

Assignee:

Notice:

US. Cl ..424/244, 424/283 Int. Cl. ..A6lk 27/00 Field of Search ..424/244, 283

51 *Jan. 30, 1973 [56] References Cited Primary Examiner-Stanley J. Friedman Att0rney-Samuel L. Welt, Jon S. Saxe, Bernard S.

Leon, Gerald S. Rosen, R. Hain Swope and William M. Farley [57] ABSTRACT Compositions comprising medazepam and propantheline halide, useful in treating gastrointestinal disorders are disclosed.

4 Claims, No Drawings MEDAZEPAM AND PROPANTHELINE COMPOSITION DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions which are therapeutically useful in the treatment of gastrointestinal disorders. Examples of gastrointestinal disor- I ders amenable to treatment by the compositions of this invention include peptic ulcer, hyperchlorhydria, ulcerative or spastic colon, nervous stomach, irritable spastic colon, mucous colitis, duidenitis, gastritis, biliary dyskinesia, pylorospasms, cardiospasm, anxiety or organic disorders of the digestive tract.

The present invention relates more specifically to compositions comprising 7-chloro-2,3-dihydro-lmethyl-S-phenyl-ZH-l ,4-benzodiazepine, hereinafter referred -to as medazepam and (2-hydroxyethyl)diisopropylmethylammonium halide xanthene- 9-carboxylate, hereinafter referred to as propantheline halide.

The combination of medazepam or an acid addition salt thereof with a pharmaceutically acceptable acid and propantheline halide has been found to be extremely effective in the therapeutic treatment of gastrointestinal disorders such as peptic ulcer and the like. This superior effectiveness is the result of the complete anticholinergic action of propantheline halide plus the ability of medazepam to effectively relieve the anxietytension syndrome often manifest with gastrointestinal disorders of the type described previously.

In addition to the free base of medazepam, any salt thereof with a conventional pharmaceutically acceptable acid, such-acid being organic or inorganic in nature, may -be utilized in forming the compositions of the present invention. For example, one can use a salt of medazepam with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like or a salt with an organic acid such as acetic acid, benzoic acid, lactic acid, malic acid, benzene or toluene sulfonic acid, maleic acid, salicylic acid and the like. The preferred salt of medazepam for forming the compositions of the present invention is the hydrochloride.

in formulating the compositions of the present invention, the term propantheline halide indicates a member of the group consisting of propantheline chloride, bromide and iodide with the bromide being preferred.

The compositions of the invention are prepared by mixing together the two active components and, optionally, pharmaceutical adjuvants, and forming the resulting mixtures into suitable oral dosage forms, e.g., pressed or coated tablets. Additionally, the compositions of the present invention can be provided in the form of hard shell capsules. If desired, the compositions of the present invention can be formulated into dosage forms suitable for parenteral administration. The methods and techniques by which these various dosage forms are prepared are the conventional procedures of the art. The applications of such procedures to the compositions of the present invention will be readily apparent to one skilled in the art. 1

In formulating the compositions of the present invention into the aforementioned dosage forms, one can use, as optional ingredients, any of the various adjuvants or excipients ordinarily employed in formulating pharmaceutical products. Thus, for example, in theforsuppository adjuvant materials, e.g., fatty acid esters of glycerine, or glycols, e.g., cocoa butter, propylene glycol monostearate, by techniques well known to the art.

The ratio of active ingredients which comprise the compositions of the instant invention may vary over a considerable range, for example, from about 5 to about 5, preferably from 1 k to about 3 parts by weight of propantheline halide for each part by weight of medazepam or salt thereof with a pharmaceutically acceptable acid. A preferred adult dosage of the active ingredients of the present invention constitutes from about 2 mg. to about 15 mg., preferably from about 5 mg. to about 10mg. of medazepam or a salt thereof with a pharmaceutically acceptable acid and from about 5 mg. to about 30 mg., preferably from about 7 5 mg. to about 15 mg. of propantheline halide. For example, one or two tablets containing as active ingredients 5 mg. of medazepam hydrochloride and 15 mg. of propantheline bromide would in most therapeutic situations be administered to an adult patient three or four times daily. Smaller dosages are, of course, utilized for children or elderly or debilitated patients. The above ranges are not critical and dosages outside these ranges can be employed since the specific dosagesand relative amounts of active ingredients depend upon the condition being treated and the needs of the patient.

The following examples are given to illustrate and not limit the invention.

EXAMPLE I .The following ingredients were blended together thoroughly to form a premix:

mg/Tablet Ingredient Mcdazepam hydrochloride 5 mg. Propantheline bromide 15 mg. Corn starch 15 mg.

The premix is then combined and blended with the following ingredients:

Ingredient mg/Tablet Microcrystalline cellulose mg. Lactose 104 mg. Magnesium stearate 1 mg.

EXAMPLE 2 The process of Example I was carried out using the same quantities of ingredients except that 10 mg. of medazepam hydrochloride was utilized in place of 5 mg. and the tablets weighed 205 mg. each.

amount EXAMPLE 3 i The following ingredients were blended thoroughly for about 15 minutes in a suitable container:

The above blend was then passed through a Fitzpatrick Comminuting Machineand then blended for an additional minutes. The mixture was then filled into hard-shell capsules, each of which contained about 195 mg. of the composition.

EXAMPLE 4 Rectal suppositories were prepared by mixing, heating and shaping the following formulation given in per suppository: 5 mg. hydrochloride, mg. of propantheline bromide, 38.45 mg. of white beeswax, 96.1 mg. of polyoxyethylene sorbitan mono-oleate (Tween 80) and 05.45 mg. of propylene glycol monostearate.

Variations in the process and compositions of the invention can be undertaken by those skilled in the art medazepam without departing from either the scope or spirit of the invention.

We'claim:

1. A therapeutic composition for the treatment of gastrointestinal disturbances in humans comprising a therapeutically inert factor consisting of a pharmaceutically acceptable carrier and a therapeutically active factor consisting of from about 1% to about 3 partsby weight propantheline halide and one part by weight of medazepam or a salt thereof with a pharmaceutically acceptable acid.

2. A therapeutic composition according to claim 1 wherein said salt of medazepam with a pharmaceutically acceptable acid is the hydrochloride salt and said propantheline halide is propantheline bromide.

3. A therapeutic composition according to claim 1 in unit dosage form suitable for internal administration wherein each unit dosage form contains 5 mg., medazepam or a salt thereof with a pharmaceutically acceptable acid and l5 mg. of propantheline bromide.

4. A therapeutic composition according to claim 1 in unit dosage form suitable for internal administration wherein each unit dosage form contains 10 mg. medaze'pam hydrochloride and 15 mg. propantheline bromide.

i l l IF 

1. A therapeutic composition for the treatment of gastrointestinal disturbances in humans comprising a therapeutically inert factor consisting of a pharmaceutically acceptable carrier and a therapeutically active factor consisting of from about 1 1/2 to about 3 parts by weight propantheline halide and one part by weight of medazepam or a salt thereof with a pharmaceutically acceptable acid.
 2. A therapeutic composition according to claim 1 wherein said salt of medazepam with a pharmaceutically acceptable acid is the hydrochloride salt and said propantheline halide is propantheline bromide.
 3. A therapeutic composition according to claim 1 in unit dosage form suitable for internal administration wherein each unit dosage form contains 5 mg., medazepam or a salt thereof with a pharmaceutically acceptable acid and 15 mg. of propantheline bromide. 